Plasma concentration-dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone-21-isonicotinate.

Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03 mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 ± 2.9 days (LLOQ: 0.025 µg/L) and in urine for 9.8 ± 3.1 days (LLOQ: 0.15 µg/L). Maximum observed dexamethasone concentration in plasma was 0.61 ± 0.12 µg/L and in urine 4.2 ± 0.9 µg/L. Terminal plasma half-life was 38.7 ± 19 h. Hydrocortisone was significantly suppressed for 140 h. The plasma half-life of hydrocortisone was 2.7 ± 1.3 h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 ± 0.04 µg/L, 0.95 ± 0.04 and 6.2 ± 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.

Effects of flunixin on cardiorespiratory, plasma lactate and stride length responses to intense treadmill exercise in Standardbred trotters.

REASONS FOR PERFORMING STUDY: Since nonsteroidal anti-inflammatory drugs, such as flunixin, on account of their anti-inflammatory and analgesic properties, are used in both racing and equestrian sport horses, the question has been raised as to whether these drugs affect the physiological responses to exercise and thus performance potential. OBJECTIVES: The aims of this investigation were to study the effects of flunixin on cardiorespiratory, metabolic and locomotor parameters in horses during intense treadmill exercise. METHODS: Six Standardbred trotters underwent an incremental treadmill exercise test to fatigue, without drug and then after administration of flunixin meglumine (1.1 mg/kg bwt i.m.). Heart rate (HR), oxygen uptake and stride length were measured and venous blood samples drawn repeatedly during the test. RESULTS: Heart rates were found to be significantly higher at submaximal speeds, while the velocity causing a HR of 200 beats/min was significantly decreased after treatment with flunixin. Maximal HR and plasma lactate concentration 5 min after exercise were unchanged after medication. Flunixin caused higher plasma lactate concentrations at all speeds and the lactate threshold was decreased, compared with baseline values. Oxygen uptake levelled off at the highest velocities and did not change after flunixin treatment. Stride length was increased after treatment, although not at the highest velocities. CONCLUSION: The increased HR and lactate responses to exercise after flunixin treatment indicate that it does influence physiological responses, but does not improve the performance potential of clinically healthy horses. However, the lengthened stride during submaximal exercise after medication could imply undetected subclinical lameness, masked in some of the horses, i.e. they have performed with a longer stride at the cost of a higher heart rate and an increased lactate concentration.

Effects of flunixin on movement and performance of standardbred trotters on the track.

An often discussed and controversial issue is the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on performance. The purpose of this study was to investigate the effect of the NSAID flunixin on the movement pattern and performance capacity of Standardbred trotters using a standardised track model. Five adult Standardbred horses in training trotted at 2 occasions with a 2 week interval on the same oval dirt track. Before each occasion the horses were either injected with flunixin meglumine (Finadyne) or normal saline solution i.m. 4 h before the performance test (double blind crossover study). The kinematics for 5 consecutive strides were filmed. There was no significant difference in maximal speed between the saline and flunixin treatment sessions. Significant changes in the movement pattern were observed as an effect of the flunixin treatment. The horses maintained the same stride duration while significantly decreasing stance time and increasing swing time in the forelimbs. The horses' range of limb angle decreased significantly. Heart rates were monitored and plasma lactate and flunixin concentrations were measured. No significant differences were found in heart rate and plasma lactate. The results indicate that flunixin had a significant effect on locomotor pattern while it did not effect metabolic response in these horses (considered to represent a normal race track population). The overall effect on performance in racing horses may therefore be related to the anti-inflammatory and analgesic properties of NSAIDs by masking pain and lameness.

Kinematics of the distal hindlimb during stance phase in the fast trotting standardbred.

Fast trotting Standardbred horses were filmed along a straight on an oval dirt track. Five consecutive stance phases were analysed to describe the planar kinematics of the distal hindlimb. The rapid changes in the geometry of the distal hindlimb that occur during the early stance phase were studied. The hoof segment was initially braked vertically and moved in the direction of the horse. The hoof moved forward on the track surface for more than 20% of the stance time (ST). Two specific deviations in the otherwise smooth course of the fetlock joint angle appeared at 16 and 29% of ST. Tarsal angular joint displacement was, on the other hand, more smooth throughout the stance phase. Segment angular velocity was greatest in the proximal pastern segment, while the metatarsus was almost totally braked in its forward rotation during the early stance. Tibial angular velocity was more smooth and greater than that of the metatarsus. Initial vertical braking of the hoof was related to the rapid rotation of the proximal pastern segment, while the metatarsal and proximal pastern segment angular velocities decreased as the hoof was braked horizontally. Also coincident with horizontal braking of the hoof was an increase in the angular velocity of the tibial segment. It was concluded that the horizontal as well as the vertical braking of the hoof affect the disto-proximal braking of the segments of the distal hindlimb during the early stance phase. The early stance phase changes in the distal hindlimb suggest rapid changes in the internal forces of the limb and should be of importance to the orthopaedic health of Standardbred trotters. These rapid changes at the fetlock joint and hock joint during the early stance may be important in lameness as excessive rapid and repetitive loading and movement are thought to induce joint damage (Radin et al. 1991).

Nonsteroidal anti-inflammatory drugs.

NSAIDs' mechanism of action by inhibiting the synthesis of prostanoids accounts for both their therapeutic and toxic effects. They are commonly used in acute and chronic musculoskeletal and soft-tissue conditions. Adverse reactions include gastrointestinal disturbances and hypoproteinemia. Their pharmacologic effect seems to have a longer duration than their plasma concentrations indicate. This gives implications on current regulations for competing horses and the relevance of permitted levels has been questioned. The NSAIDs do not appear to enhance performance, but rather allow the horse to run up to its potential by reducing pain and lameness. There is concern over the possible hazards to the horse by this kind of therapeutic use. In conclusion, NSAIDs have well justifiable therapeutic uses in equine practice. They should, however, be used when there is a clear clinical indication, in safe dose rates and without jeopardizing the welfare of the performance horse.

Application of TrackEye in equine locomotion research.

TrackEye is an analysis system, which is applicable for equine biokinematic studies. It covers the whole process from digitizing of images, automatic target tracking and analysis. Key components in the system are an image work station for processing of video images and a high-resolution film-to-video scanner for 16-mm film. A recording module controls the input device and handles the capture of image sequences into a videodisc system, and a tracking module is able to follow reference markers automatically. The system offers a flexible analysis including calculations of markers displacements, distances and joint angles, velocities and accelerations. TrackEye was used to study effects of phenylbutazone on the fetlock and carpal joint angle movements in a horse with a mild lameness caused by osteo-arthritis in the fetlock joint of a forelimb. Significant differences, most evident before treatment, were observed in the minimum fetlock and carpal joint angles when contralateral limbs were compared (p < 0.001). The minimum fetlock angle and the minimum carpal joint angle were significantly greater in the lame limb before treatment compared to those 6, 37 and 49 h after the last treatment (p < 0.001).

Studies of meclofenamic acid and two metabolites in horses--pharmacokinetics and effects on exercise tolerance.

The pharmacokinetics and the effects on treadmill exercise of the anti-inflammatory drug meclofenamic acid were studied in seven Standardbred horses after single intravenous and/or oral doses. The decline in plasma concentration after a single intravenous dose of meclofenamic acid (2.2 mg/kg b.wt) was described by a two-compartment open model. The average elimination half-life was 1.4 h, the apparent volume of distribution 0.14 l/kg and the plasma clearance 0.12 l/h kg. Absorption was the rate-limiting step after oral administration. Non-compartmental analysis showed a mean absorption time of 4.3 h. The pharmacokinetics of two metabolites of meclofenamic acid were also studied in two of the horses. The elimination half-lives of the two metabolites were virtually the same in each horse (3.0 h and 3.4 h). The blood lactate response to exercise was significantly decreased after treatment with meclofenamic acid, indicating a lower utilization of the glycolytic ('anaerobic') energy contribution during exercise. Circulatory capacity was apparently unaffected with an unchanged heart rate response to exercise.

Clenbuterol plasma concentrations after repeated oral administration and its effects on cardio-respiratory and blood lactate responses to exercise in healthy Standardbred horses.

To evaluate the effects of clenbuterol on cardio-respiratory parameters and blood lactate relation to exercise tolerance, experimental horses performed standardized exercise tests on a high-speed treadmill before and after administration of the drug. Clenbuterol was administered in feed to six healthy Standardbreds at a dose rate of 0.8 micrograms/kg b.wt twice daily for 5.5 days. Each horse was tested twice, without and with a respiratory mask, during two consecutive days. One week elapsed between the baseline tests without drug and the tests with clenbuterol treatment (each horse served as its own control). The results show an unchanged heart rate response to exercise 2 h after the last clenbuterol administration. The blood lactate response and the arterial oxygen tension during exercise did not differ before and after drug treatment. The oxygen uptake as well as pulmonary ventilation relative to the work load performed was essentially unaffected. The arterial pH during exercise was significantly increased (P less than 0.05) following clenbuterol treatment. Plasma levels of clenbuterol were maximal 2 h post-administration with values between 0.45 and 0.75 ng/ml. The plasma half-life of elimination was 10.4 h (+/- 2.25 SD). In conclusion, clenbuterol did not cause any major effects on the cardio-respiratory and blood lactate parameters studied in healthy horses performing submaximal exercise tolerance tests.

Pharmacokinetics and cardio-respiratory effects of oral theophylline in exercised horses.

The pharmacokinetics of theophylline at rest and the effects on cardio-respiratory and blood lactate responses to exercise were investigated after repeated oral administrations in six healthy Standardbred horses. A dose of 5 mg/kg body weight was administered every 12 h. The binding of theophylline to plasma protein was also determined. There was good agreement between predicted and observed plasma concentrations of theophylline at steady state. The mean half-life of elimination was shown to be 17.0 +/- 2.5 h, the mean half life of absorption was 1.6 +/- 1.8 h, the apparent volume of distribution was 852 +/- 99.0 ml/kg and total plasma clearance 0.61 +/- 0.08 ml/kg/min. Theophylline showed very low plasma protein binding (12%). The heart rate and blood lactate levels, during and after exercise, were significantly increased during theophylline-treatment. There was an increase of the arterial oxygen tension after exercise and the arterial carbon dioxide values before and after exercise were significantly lower than the premedication values. No severe adverse effects of the drug were noted. The recommended oral dose is therefore 5 mg/kg every 12 h but due to inter-individual variation, an adjustment of the dose may be necessary. The changes in the studied exercise parameters indicate that the performance capacity may be impaired by theophylline in the healthy horse.

Cardiorespiratory and sedative effects of a combination of acepromazine, xylazine and methadone in the horse.

Cardiorespiratory and sedative effects of a combination of acepromazine, xylazine and methadone were studied in the horse. Acepromazine and xylazine produced cardiovascular effects whereas methadone mainly affected respiratory rate. Decreases in heart rate, arterial blood pressure and respiratory rate were seen. Sedation was superior to that of acepromazine, xylazine or a combination of these. No serious side effects were seen.